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Clinical Trials |
Imperial Cancer Research Fund Medical Oncology Unit, and Department of Urology, Churchill Hospital, Oxford OX3 7LJ, United Kingdom [J. P. B., K. J. O., D. J. P., M. S., N. D., C. H., J. W., K. M., J. C., K. S., T. S. G., D. C. T., A. L. H.]; Haemostasis, Thrombosis and Vascular Biology Laboratory, University Department of Medicine, City Hospital, Birmingham, B18 7QH, United Kingdom [A. B.]; and Finsen Laboratory, Righospitalet, DK-2100, Copenhagen, Denmark [R. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, the
overall results in randomized Phase III studies are disappointing with
only modest improvements in overall survival. This Phase II study
evaluated the efficacy and tolerability of razoxane, an antiangiogenic
topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age:
range, 31–76 years; median, 58 years) with inoperable RCC. Twenty
patients received razoxane 125 mg p.o., twice a day for 5
days each week for 8 weeks (one cycle). This was repeated in patients
with stable disease (StD), but was discontinued after 16 weeks
if there was no evidence of an objective response. Because minimal
toxicity was seen, subsequent patients (n = 20)
were treated until progressive disease (PD) was documented. Of 38
evaluable patients, 11 (29%) had StD for a minimum of 4 months, and
the remainder had PD. Median overall survival was 7.3 months. Duration
of survival was significantly better in patients with StD compared with
those with PD (P = 0.003). The effect of treatment
on six potential surrogate serum/plasma (vascular endothelial growth
factor (VEGF), basic fibroblast growth factor (bFGF), urokinase
plasminogen activator soluble receptor (uPAsr), E-selectin, vascular
cell adhesion molecule-1 (VCAM-1) and von Willebrand’s factor (vWF)
and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated
before and after 1 cycle of treatment. Pretreatment serum VEGF and
E-selectin levels above the median value were associated with a poor
prognosis. Serum VCAM-1 levels and urinary VEGF levels rose
significantly after one cycle in patients with PD but not in those with
StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF
levels were significantly higher in PD patients compared with StD
patients before and/or after 1 cycle of treatment. In conclusion,
razoxane is an antiangiogenic agent that has minimal toxicity and that
requires further evaluation in combination with other active agents in
the treatment of RCC. Surrogate serum and urinary markers of
angiogenesis may have a role to play in predicting disease response and
overall survival in RCC. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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9%.
Radiotherapy may be used in the palliation of symptoms but likewise is
associated with a poor response rate (1, 2, 3, 4, 5, 6)
. Razoxane (ICRF 159; (±)1,2-di(3,5-dioxopiperazin-1-yl) propane) belongs to the family of bis-dioxopiperazines, developed in the 1960s as derivatives of the chelating agent EDTA. Early in its development it was shown to have potent antiangiogenic activity, with vessels at the periphery of tumors reverting from an abnormal tumor-related vasculature to a normal phenotype (7, 8, 9, 10) . The precise molecular mechanism of this antiangiogenic action is not known. More recently razoxane has been shown to be a noncleavable inhibitor of topoisomerase II (11) . Razoxane inhibits metastatic spread of Lewis lung 3LL, hamster lymphoma ML, and murine squamous carcinoma G cells in experimental animals and causes a marked increase in the sensitivity of tumors to radiation (reviewed in Refs. 12 and 13 ). Initial Phase I and II clinical trials demonstrated modest antitumor activity in advanced colorectal and head and neck carcinomas, lymphomas, lymphosarcomas, and acute leukemias. In combination with radiotherapy, razoxane has activity against liver metastases from colorectal, inoperable nonmetastatic rectal, bladder, vulval, and lung carcinomas; soft tissue and osteosarcomas; and central nervous system tumors including malignant glioma and astrocytoma (reviewed in Refs. 12 and 13 ).
Razoxane is absorbed from the gastrointestinal tract in a schedule-dependent manner. Absorption is poor with large single doses but is satisfactory with small divided doses (14) . The plasma half-life in humans is 3.5 h. It is well tolerated with few side effects seen in early clinical trials. However, with high-dose razoxane, neutropenia and thrombocytopenia are seen (15) because of the topoisomerase activity and inhibition of cell proliferation. Hematological toxicity was rarely seen with prolonged low-dose schedules and razoxane was well tolerated when evaluated in the adjuvant treatment of colorectal carcinoma at a dose of 125 mg b.d. p.o. for 5 days every week given for up to 2 years, (16 , 17) . As such, oral razoxane is an inexpensive antiangiogenic and antiproliferative agent with few side effects.
Angiogenesis, the process of new microvessel formation, is necessary
for a tumor to grow beyond 1–2 mm in diameter. Neovascularization also
plays an important role in the metastatic spread of malignant disease
(18)
. New vessel formation, with accentuation of capsular
vessels, is a feature of RCC (19)
. High microvessel counts
in RCC are associated with a poor prognosis (20
, 21)
.
IFN- and IL-2 are antiangiogenic. This observation may in part
explain their antitumor activity in RCC (22
, 23)
.
Therefore, investigation of inexpensive, established agents with
antiangiogenic properties requires evaluation in the management of RCC.
Angiogenic growth factors and their receptors, proteases and protease
receptors, and endothelial cell adhesion molecules play important roles
in the pathogenesis of malignant tumors. These factors include VEGF
(24)
, bFGF (25
, 26)
, uPAsr (27)
,
E-selectin, VCAM-1 (28)
, and vWF (29)
.
Elevated levels of these proteins may be detected in the blood and
urine of patients with malignant disease (28, 29, 30, 31, 32, 33)
.
The purpose of this study was to evaluate the efficacy of prolonged low-dose oral razoxane in the treatment of metastatic RCC. Antiangiogenic agents may not produce regression of established blood vessels; therefore, we considered StD to be a relevant end point. Treatment with antiangiogenic drugs may be required over a protracted period of time; therefore, we wanted to assess whether it was possible to detect antiangiogenic effects early in the course of treatment. We hypothesized that potential surrogate plasma/serum and urine markers of angiogenesis would be influenced by therapy and would predict subsequent disease status.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 years; WHO performance
status, 2; expected survival, 3 months; hemoglobin, 10 g/dl;
white blood count, 3 x 109/liter;
absolute neutrophil count, 2 x 109/liter;
platelet count, 100 x 109/liter;
bilirubin, 2 x normal; AST/ALT, 3 x normal (unless
because of metastases, in which AST/ALT 5 x normal is
accepted); and creatinine within the normal range for our institution
(70–150 µmol/liter, Oxford Radcliffe Hospital). Patients with
previous or intercurrent malignancies at other sites, with the
exception of adequately treated cone-biopsied carcinoma of the cervix
and basal or squamous cell carcinoma of the skin were excluded from the
study. Other exclusion criteria were intensive chemotherapy or
radiotherapy <3 weeks before inclusion, pregnancy, or women likely to
become pregnant during the trial. Patients of childbearing age had to
take adequate contraceptive precautions during the trial and for 4
weeks after completing treatment. The study was approved by the Central
Oxford Research Ethics committee and conducted according to the
recommendations of the Declaration of Helsinki and the Association of
British Pharmaceutical Industry guidelines for good clinical
practice. Informed written consent was obtained from each patient prior
to entry into the study.
Patient Evaluation.
In the 3 weeks prior to commencing treatment, each patient had the
following assessments: physical examination with clinical evaluation of
all of the sites of disease; a full blood count and renal, liver, and
bone biochemistry screen; and establishment of a measurable lesion(s)
using additional investigations as clinically indicated (plain X-rays,
ultrasound, computed tomographic imaging, magnetic resonance
imaging). On the day of prescription of razoxane, the patient had a
further clinical evaluation. A full blood count was checked every 2
weeks while the patient was on study. Each patient was reexamined every
4 weeks and at each time had a biochemistry profile.
Treatment Schedule.
In the first 20 patients recruited to the study, 125 mg razoxane was
administered b.d. p.o. for 5 days a week for a cycle duration of 8
weeks. After formal disease assessment, the cycle was repeated in
patients with either StD or responding disease and discontinued after
16 weeks (two cycles) if there was no evidence of objective disease
response. Because the agent was well tolerated in these patients,
subsequent patients were treated until PD was documented.
Toxicities and Dose Modifications.
Toxicity was graded according to the Cancer and Leukemia Group
B expanded CTC. Treatment delay of 1 week’s duration was
considered for any grade 2 toxicity apart from anemia,
alopecia, and nausea and vomiting controlled with antiemetics. If the
grade 2 toxicity persisted for >1 week or if > grade 3
neutropenia occurred, the treatment was reduced by 30% with razoxane
125 mg once a day on days 1, 3, and 5 and 125 mg b.d. on days 2
and 4 of the 5-day schedule. Razoxane treatment was discontinued if a
further dose reduction was indicated, if grade 4 toxicity (CTC scale)
was experienced at the reduced dose level, or if a life-threatening
event occurred that was deemed directly related to razoxane therapy.
Response Assessment.
The assessable lesion/lesions were clearly measurable according to CRC
recommendations. A lesion was considered measurable if it measured 1
cm in diameter on computed tomographic or magnetic resonance imaging,
or at least 2 cm on plain X-ray or ultrasound, in each of two
perpendicular dimensions. The established measurable lesion(s) were
evaluated after each 8-week cycle to assess response. A CR was defined
as clearance of all of the measurable or evaluable disease for 8
weeks. A PR was defined as a reduction in the sum of the product of all
of the bidimensional measurements of the lesions evaluated at baseline
by 50% for 8 weeks. Disease was considered stable if the lesions
measured at baseline reduced in size by <50% or increased by <25%
after two cycles of treatment. PD was defined as an increase of 25%
in the sum of the product of the bidimensionally measurable disease
sites, or the appearance of new metastases <16 weeks (two cycles)
after commencing razoxane.
Surrogate Blood and Urine Markers of Angiogenesis.
Prior to treatment, two 10-ml blood samples for serum and plasma, and a
urine sample, were obtained to analyze potential surrogate markers of
angiogenesis. The blood sample was chilled on ice, centrifuged at 2000
rpm for 10 min at 4°C and stored in 1.5-ml aliquots at -70°C until
analysis. The urine samples were either brought in by the patient or
taken fresh on the morning of treatment and were frozen at -70°C
until analysis. Additional samples were obtained after 4 and 8 weeks (1
cycle) of treatment.
Serum E-selectin, VCAM-1, and serum and urine bFGF and VEGF were measured using ELISA kits supplied by R&D systems (Abingdon, United Kingdom). The serum vWF and plasma uPAsr levels were analyzed by ELISA using in-house methods as described previously (31 , 34) . The normal range (or mean ± SD) for each assay was as previously published or determined as indicated: serum VEGF, 62–707 pg/ml (mean, 220 pg/ml)4 ; urinary VEGF, 73–144 ng/g creatinine (32) ; serum bFGF, 0–4.4 pg/ml4 ; urinary bFGF, 0.6–8.1 ng/g creatinine (33) ; and plasma uPAsr, 0.83–1.7 ng/ml (31) . For uPAsr, a control population without cancer (n = 57; range, 1.09 ± 0.76) were analyzed at the same time as the razoxane patients samples. Analysis of VCAM-1, vWF, and E-selectin was made in comparison with a historical control population without cancer (n = 186) previously assayed: serum VCAM-1, 525 ± 173 ng/ml; serum E-selectin, 48.37 ± 19.6 ng/ml; serum vWF, 103 ± 30 IU/dl. All of the interassay coefficients of variation were <10% and intra-assay coefficients were <5%.
Statistical Methods.
The Wilcoxon rank-sum test was used to analyze differences in surrogate
markers before and after one cycle of chemotherapy within the StD and
PD groups. The Mann-Whitney test was used to test for differences in
the markers between patients with StD and PD. Fisher’s exact test was
used for testing relationships between categorical variables and
Student’s t test to compare pretreatment angiogenic marker
levels with control values as appropriate. The analysis was performed
using the Stata statistical software, release 5.0 package (Stata Corp.,
College Station, TX).
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Only five patients had received previous treatment, and of these, only
one had received cytokine therapy using IL-2.
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16 weeks’ duration. All of these
patients were either newly diagnosed (n = 4) or had
evidence of objective tumor progression in the 6 months prior to
starting treatment (n = 7). The median survival for all
of the 40 patients included in the study was 7.3 months. In evaluable
patients, the median survival for those with StD was 399 days and for
the 27 patients with PD, 127 days (P = 0.0026). The TTP
was 12 weeks.
Patients were characterized as having a good, moderate, or poor
prognosis based on the criteria of Jones et al.
This involves the application of a simple index based on the
presence or absence of each of the following three risk factors:
performance status 1 (rather than 0); time from diagnosis <2 years;
and more than one site of metastases. Good-prognosis patients have 1
risk factor; moderate-prognosis patients, any two risk factors; and
poor-prognosis patients, all three risk factors. Of the 40 patients
studied, 9 had good prognostic features, 18 had moderate, and 13 had
poor. Although the good prognostic group had a better overall survival,
this was not statistically significant. Of the 38 evaluable patients,
no association was found between the prognostic groups and the
development of PD. Three of 9, 5 of 18, and 3 of 11 patients had StD
16 weeks in the good, moderate, and poor prognostic groups,
respectively. Elevated pretreatment neutrophil counts (>8.25 x
109/liter; P = 0.016), lactate
dehydrogenase levels (>170 IU/liter; P = 0.016), and
platelet counts (>450 x 109/liter;
P = 0.015), above the median for the patient group,
were associated with a poor prognosis as reported previously (4
, 35)
. An unresected primary tumor (P = 0.08), the
presence of bone metastases (P = 1) or
extrapulmonary metastases (P = 1), or a hemoglobin <10
g/dl (P = 0.366) lacked prognostic significance.
Toxicity and Dose Modifications.
Toxicity is summarized in Table 2
. Grade 3 toxicity was rare and included neutropenia (three patients),
nausea and vomiting (one patient), and fatigue and diarrhea (one
patient each). One patient had a delayed hypersensitivity
reaction to razoxane characterized by the development of an urticarial
rash and arthritis, whereas another developed cerebellar symptoms after
three cycles of treatment. In both cases, the symptoms resolved on
withdrawal of the drug. Treatment was delayed in 10 patients because of
neutropenia (8 patients), continuing vomiting (1 patient), and
mucositis (1 patient). The dose was reduced by 30% in four patients on
one occasion only, because of grade 3 or persistent grade 2
neutropenia.
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and Table 3
. Serum VEGF levels were analyzed in 35 patients before treatment.
Elevated levels above the normal range were seen in 12 (34%).
Pretreatment levels were significantly higher in patients who
subsequently developed PD compared with those with StD
(P = 0.042). No change in overall values, either for
the whole group or for those with StD or PD, was seen during the first
cycle of treatment. Patients with pretreatment serum levels above the
median for the group had a worse prognosis (P = 0.023).
A significant correlation was seen between pretreatment serum VEGF
levels and platelet counts (P < 0.0001; correlation
coefficient, r, 0.69). Urinary VEGF levels were analyzed in
34 patients and were elevated in 10 prior to treatment (30%). A
significant rise in urinary VEGF levels was seen in patients who
developed PD (P = 0.006) but not in those with StD
(P = 0.09).
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uPAsr levels were elevated in patients (mean ± SD, 1.95 ± 1.4 µg/liter) compared with a normal control population (1.09 ± 0.72 µg/liter; P = 0.0001) with 12 (37%) of 32 having elevated levels pretreatment. There was a trend for levels to increase with razoxane therapy in the PD group and to fall in the StD group. Levels were significantly higher in the PD as compared with the StD group before (P = 0.04) and after (P = 0.028) 1 cycle of treatment.
Pretreatment serum VCAM-1 levels were significantly higher in patients compared with our control population [717 ± 303 versus 525 ± 173 ng/ml (mean ± SD); P = 0.0001]. Levels rose significantly in patients with PD (P = 0.039) being higher than those in patients with StD after treatment (P = 0.031). Although no significant differences were found in E-selectin levels between patients and the normal range [52 ± 20 versus 48 ± 19 ng/ml (mean ± SD); P = 0.22] or in the StD and PD groups before or after treatment, E-selectin levels above the median were associated with a worse outcome (P = 0.022). Pretreatment vWF levels were elevated in 6 (17%) of 35 patients. No significant difference was seen between vWF levels in patients and our controls [107 ± 53 versus 103 ± 30 IU/dl (mean ± SD); P = 0.112]. Although no significant change in levels was seen on treatment, values in patients with PD were significantly higher than those with StD, both before (P = 0.026) and after (P = 0.024) one cycle of razoxane.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This raises the issue as to how we should assess the effectiveness of antiangiogenic therapy. The drugs being considered for this role are, in general, cytostatic rather than cytotoxic to endothelial cells, inhibiting their proliferation and/or elongation (36) . It seems reasonable to suppose that tumor stabilization or reduced tumor-growth kinetics, with a resultant prolongation of survival, would be realistic end points in terms of tumor response evaluation. If StD is considered a valid end point, then the response rate with razoxane in the treatment of RCC is similar to those seen in recent studies of other potential antiangiogenic drugs. Eighteen of 66 patients recruited to a Phase II study of low-dose continuous thalidomide had RCC; of these, 3 had a PR and another 3 had StD, giving a 33% response rate (CR + PR + StD; Ref. 37 ). Likewise in a Phase I dose-escalating study of IL-12 (38) and a Phase II study of TNP-470 (39) , 8 (29%) of 28 and 7 (21%) of 33 patients responded to treatment.
These results are comparable with those from three randomized trials
with IL-2 and IFN. In the study comparing IL-2, IFN-, and IL-2 plus
IFN-, the event-free survival of all of the 3 arms was 10 weeks,
whereas the response rate (CR + PR + StD) in evaluable patients was 33,
40, and 48%, respectively, at 10 weeks and 12, 19, and 20% at 25
weeks (5)
. In the trial comparing IFN- and
medroxyprogesterone acetate the progression-free survival of each group
was 4 and 3 months, respectively; however, the overall response rates
are difficult to determine (6)
. Finally, in the study
comparing IFN-
with placebo, TTP for both arms was 1.9 months, with
a best response at 8 weeks of 37 and 36%, respectively
(40)
. By comparison, 47, 29, and 13% of the patients in
our study had StD at 8, 16, and 24 weeks, respectively, whereas TTP was
12 weeks. These findings suggest that StD is an important end point for
assessment of antiangiogenic agents and that, in this Phase II study,
razoxane had activity that was comparable with more established
treatments. Additional randomized trials with antiangiogenic agents,
including razoxane, are warranted.
The evaluation of surrogate serum, plasma, and urinary markers of
endothelial function or angiogenesis may have a role to play in
assessing the efficacy of novel antiangiogenic drugs (36)
.
Pretreatment serum VEGF and E-selectin levels above the median value
were directly associated with a worse prognosis, as previously reported
in other studies (41
, 42)
. A significant rise in urinary
VEGF levels was seen in patients with PD (Table 3)
, but this rise was
not significant when compared with the StD patients (Fig. 1
B). No correlation was seen between serum and urinary VEGF
levels, or between urinary levels and the presence of the primary
tumor. This is in keeping with previous work in bladder cancer
(32)
.
Plasma uPAsr levels were higher in patients with RCC than in a normal control population. uPAsr was significantly elevated in patients who developed PD on razoxane compared with those with StD both before treatment and after 8 weeks and, therefore, is not serially predictive of which patients will respond. Similarly vWF, urine bFGF, and serum VEGF were significantly different pretreatment in patients who developed PD compared with those with StD but this did not alter after treatment and, thus, cannot be used as a marker of response to razoxane therapy.
However, serum VCAM-1 and serum bFGF showed no difference between
patient groups before treatment; but, after therapy with razoxane,
there was a significant difference between patients with PD compared
with those with StD. This was attributable to a rise in VCAM-1 in
patients with PD and a small fall in patients with StD (Fig. 1
F) and to a rise in bFGF in patients with PD (Fig. 1
C). These results underline those of previous studies
showing VCAM-1 to be elevated in patients with solid tumors, including
breast, renal, colorectal, gastric, and ovarian cancer and malignant
melanoma, and its association with disease progression and a poor
prognosis (28
, 35 , 43, 44, 45)
. The significant rise in serum
VCAM-1, urinary VEGF, and serum bFGF levels seen in patients with PD
indicates that these angiogenic growth factors should be further
evaluated as potential surrogate markers of tumor response in RCC and
in malignant diseases in general. Although these results have to be
interpreted with caution, markers of endothelial cell proliferation and
protease activation may be useful in suggesting possible molecular
mechanisms of action for razoxane on endothelial cells. This requires
further investigation in the preclinical setting. Further clinical
evaluation of the antiangiogenic effect of razoxane could be provided
by looking at tissue staining for surrogate markers and by using
noninvasive radiology (e.g., positron emission tomography
scans).
The prognostic significance of the absolute neutrophil count, platelet counts, and lactate dehydrogenase levels seen in this study is well established for malignant diseases including RCC (4 , 46) . A significant correlation was found between pretreatment platelet counts and serum VEGF levels. Platelets transport and, after activation, release VEGF. Intratumoral platelet activation may result in the release of high local concentrations of the angiogenic growth factor and induce tumor angiogenesis. Therefore, serum VEGF may be an important marker for VEGF that could be delivered to tumors by platelets (47) . In our study, elevated serum VEGF was associated with a worse prognosis. VEGF can induce the release of vWF from endothelial cells (48) . We found no correlation between VEGF and vWF levels in our patients, or between vWF and platelet counts.
Razoxane, at the dose schedule used in this study, was well tolerated.
Grade 3 toxicities were rare and included nausea and vomiting in one
patient, diarrhea in one, neutropenia in three, and fatigue in another.
As such, the side-effect profile was in keeping with that expected for
razoxane (12)
apart from two patients: one who developed
cerebellar symptoms and the other, a delayed hypersensitivity reaction
(Table 2)
. Some concern has been expressed that prolonged treatment
with razoxane may predispose to acute promyelocytic leukemia (APL) and
acute myeloid leukemia. Whereas in many of these cases patients
received a variety of drugs prior to razoxane therapy, APL has
developed in chemotherapy-naive patients (13
, 49)
.
Although this does not necessarily imply cause and effect, it may be
important if razoxane is used for prolonged therapy.
Antiangiogenic agents, including razoxane, have been shown to enhance
the antitumor activity of cytotoxic drugs (18)
. The
combination of two or more antiangiogenic agents with different modes
of action may further enhance this effect, e.g., TNP-470, an
inhibitor of endothelial cell proliferation, and minocycline, an
inhibitor of gelatinase activity, combined with cyclophosphamide
(50)
. The combination of razoxane with agents with
antiangiogenic/immunomodulatory activity such as the
cytokines—IFN-, IL-2, and IL-12—and thalidomide would appear to be
particularly attractive in the setting of RCC.
In conclusion, razoxane is a well-tolerated, antiangiogenic topoisomerase II inhibitor that may have a role to play in the management of solid, cytotoxic chemotherapy-resistant, tumors. Serum VCAM-1, urinary VEGF, and serum bFGF were identified as the most promising potential markers of response to antiangiogenic therapy. Because of the favorable toxicity profile, razoxane should be considered for combination studies with other antiangiogenic, biological, and cytotoxic agents in the treatment of RCC, both in the experimental setting and in clinical studies. Surrogate markers to assess the antiangiogenic activity of any drug in the treatment of solid tumors require further evaluation.
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FOOTNOTES |
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1 This work was supported by the Imperial Cancer
Research Fund (ICRF). 
2 To whom requests for reprints should be
addressed, at ICRF Medical Oncology Unit and Molecular Oncology
Laboratory, Institute of Molecular Medicine, John Radcliffe Hospital,
Oxford, OX3 9DS, United Kingdom. Phone: 44-1865-222457; Fax:
44-1865-222431; E-mail: aharris.lab{at}icrf.icnet.uk
3 The abbreviations used are: RCC, renal cell
cancer; VEGF, vascular endothelial growth factor; bFGF, basic
fibroblast growth factor; uPAsr, urokinase plasminogen activator
soluble receptor; VCAM-1, vascular cell adhesion molecule-1; vWF, von
Willebrand’s factor (antigen); PD, progressive disease; StD, stable
disease; TTP, time to tumor progression; b.d., twice a day; IL,
interleukin; ASP, aspartate aminotransferase; ALT, alanine
aminotransferase; CTC, common toxicity criteria; CR, complete response;
PR, partial response.
4 R&D Systems, personal communication.
Received 6/27/00; revised 9/28/00; accepted 10/ 3/00.
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 R. M. Tuttle, M. Fleisher, G. L. Francis, and R. J. Robbins Serum Vascular Endothelial Growth Factor Levels Are Elevated in Metastatic Differentiated Thyroid Cancer but Not Increased by Short-Term TSH Stimulation J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1737 - 1742. [Abstract] [Full Text] [PDF]
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R. S. Kerbel Clinical Trials of Antiangiogenic Drugs: Opportunities, Problems, and Assessment of Initial Results J. Clin. Oncol., September 15, 2001; 19(90001): 45s - 51. [Full Text] [PDF]
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A. L. Harris, P. Reusch, B. Barleon, C. Hang, N. Dobbs, and D. Marme Soluble Tie2 and Flt1 Extracellular Domains in Serum of Patients with Renal Cancer and Response to Antiangiogenic Therapy Clin. Cancer Res., July 1, 2001; 7(7): 1992 - 1997. [Abstract] [Full Text] [PDF]
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